Sustained-release delivery systems for therapeutic agents have received a considerable amount of attention in recent years. Examples include controlled-release injectable and oral formulations, transdermal patches, and implantable depot formulations. Such systems are of particular interest as a means of delivering therapeutic proteins.
When producing formulations of therapeutic proteins, it is important to preserve the physical, chemical, and biological properties of the protein. In contrast to lower molecular weight drugs, proteins typically have large globular structures, including secondary, tertiary, and in some cases, quaternary structural features that are important for biological activity. Furthermore, proteins have labile bonds and chemically reactive groups on their side chains which are susceptible to oxidation (methionine, tryptophan, histidine, tyrosine), deamidation (arginine, glutamine) or disulfide reduction or interchange (cysteine). In addition to preserving biological activity, it is particularly important to reduce or eliminate protein alterations that increase the protein's immunogenicity. Undesired immune responses can lead to safety concerns, and neutralizing antibody responses can limit the efficacy of subsequent treatments. Thus, the need to stabilize therapeutic proteins for long periods in a physiological environment has been an obstacle to the development of sustained-release protein delivery systems.
One way to stabilize drugs is to embed them in biodegradable polymeric microparticles (Maulding (1987), J. Controlled Release 6:167-176; Smith et al. (1990), Advanced Drug Delivery Reviews 4:343-357; Holland et al. (1986), J. Controlled Release 4:155-180; Lewis et al. (1990), Biodegradable Polymers as Drug Delivery Systems, pp. 1-41, Dekker, New York.) Studies using microparticles made from homo- and co-polymers of lactic and glycolic acid (PLGA polymers) have shown that these polymers hydrolyze to acid monomers (Maulding (1987), J. Controlled Release 6:167-176; Smith et al. (1990), Advanced Drug Delivery Reviews 4:343-357; Cower et al. (1985), Methods in Enzymology 112:101-116) and are chemically unreactive under the conditions used to prepare the microparticles. Such polymers can be produced in a range of molecular weights and monomer ratios which allows adjustment of the drug release rate to the particular application. PLGA polymers are non-immunogenic and non-toxic. These properties led to the selection of a PLGA polymer for use in the depot formulation of the luteinizing hormone releasing hormone (LHRH) agonist luprolide (Sanders et al. (1986), J. Pharm. Sci. 75:356-360; Ogawa et al. (1988), Chem. Pharm. Bull. 5:1095-1103; Ogawa et al. (1988), Chem. Pharm. Bull. 36:2576-2581). Johnson et al. (1997), Pharmaceutical Research 14:730-735, stabilized recombinant human growth hormone by forming a zinc-protein complex and encapsulated the complex in the solid state into PLGA microparticles (see also PCT Application No. PCT/US95/05511, Publication No. WO 95/29664).
Despite their advantages for stabilizing proteins, the administration of polymer-based drug formulations can be problematic. For example, the dose is limited by the amount of the formulation that can readily be suspended and injected. In formulations containing particles, aggregation or dilatancy can lead to clogging of the needle, making it difficult to administer the intended dose. In an effort to reduce agglomeration, excipients such as carboxymethylcellulose (CMC), dextran, or sorbitol have been included in the injection vehicle. Surfactants and salts have also been added in an effort to alter the particles' fluid properties. CMC, Tween™, and phosphate-buffered saline have been used in a vehicle for delivering a lupron depot formulation. However, the doses of this formulation are relatively small: 30-60 mg of microparticles each. In general, it is difficult to inject doses greater than 200 mg/mL of microparticles through a 21- or 23-gauge needle. Assuming a maximum subcutaneous dose of 1 mL, the maximum microparticle dose is 200 mg. The use of such large-bore needles increases the pain of injection, but the use of smaller bore needles further restricts the dose that can be delivered in a single injection.
An injection vehicle that enhanced the injectability of particulate suspensions, generally, and/or polymer-based drug formulations, in particular, would allow delivery of higher doses of drug and/or allow the use of smaller needles. These benefits would increase the feasibility of polymer-based formulations for a wider variety of therapeutic applications.